Synthesis of N-substituted 1,2,5-thiadiazolidine and 1,2,6-thiadiazinane 1,1-dioxides from primary amines

Article abstract of DOI:10.1016/S0040-4039(03)01269-3

Alkyl and aryl N-substituted 1,2,5-thiadiazolidine and 1,2,6-thiadiazinane 1,1-dioxides 6 were synthesized in good yields from the reaction of sulfuryl chloride with 2-chloroethylamine or 3-chloropropylamine hydrochlorides, respectively, followed by treatment with a primary amine and triethylamine, and ring closure with K₂CO₃ in DMSO.

Full text of DOI:10.1016/S0040-4039(03)01269-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5483–5485
Synthesis of N-substituted 1,2,5-thiadiazolidine and
1,2,6-thiadiazinane 1,1-dioxides from primary amines
Paul D. Johnson,a,* Sarah A. Jewellb and Donna L. Romeroa
aMedicinal Chemistry, Pharmacia, Kalamazoo, MI 49001, USA
bAlma College, Alma MI 48801, USA
Received 24 April 2003; revised 21 May 2003; accepted 21 May 2003
Abstract—Alkyl and aryl N-substituted 1,2,5-thiadiazolidine and 1,2,6-thiadiazinane 1,1-dioxides 6 were synthesized in good
yields from the reaction of sulfuryl chloride with 2-chloroethylamine or 3-chloropropylamine hydrochlorides, respectively,
followed by treatment with a primary amine and triethylamine, and ring closure with K2CO3 in DMSO. © 2003 Elsevier Science
Ltd. All rights reserved.
We recently required access to a wide variety of N-aryl
1,2,5-thiadiazolidine 1,1-dioxides. A convenient access
to five-membered cyclosulfamides starting from chloro-
sulfonyl isocyanate and chloroethylamines followed by
5-exo-tet closure with base has been reported (Scheme
1).1 N-Aryl cyclosulfamides were not reported,
although they may be available by this route if the
requisite N-aryl nitrogen mustards or N-aryl glycine
esters were available. Older methods are not general
and the reaction conditions are usually harsh and yields
are low.2
reaction of mono(chloroalkyl)sulfamyl chlorides with
aryl amines followed by ring closure of the resulting
chloroalkyl sulfamide, vida supra. We report herein a
versatile synthesis of five- and six-membered N-alkyl
and N-aryl cyclosulfamides from readily available pri-
mary amines.
Monoalkylsulfamyl chlorides have been reported to be
prepared from primary alkylamine hydrochlorides and
a large excess of sulfuryl chloride.3 We found that when
2-chloroethylamine hydrochloride or 3-chloropropyl-
amine hydrochloride were heated at 75–80°C for about
18 h with 6 equiv. of sulfuryl chloride in acetonitrile the
corresponding mono(chloroalkyl)sulfamyl chlorides 3
were obtained (Scheme 2). Concentration in vacuo and
extraction with diethyl ether separated the product 3
from any unreacted amine hydrochloride. This ether
solution was added dropwise to a solution of 0.6 equiv.
of a primary amine 4 and 2 equiv. of triethylamine in
diethyl ether at −70°C. The mixture was stirred at room
temperature for 4 h, then washed with water and dried
to give the N-alkyl or N-aryl (chloroalkyl)sulfamides 5.
We envisioned that an attractive approach to a general
synthesis of the title compounds would involve the
Scheme 1.
Scheme 2.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01269-3

5484
P. D. Johnson et al. / Tetrahedron Letters 44 (2003) 5483–5485
Treatment of 5 with 1 equiv. of potassium carbonate in
DMSO gave the final products 6. Isolated yields of
22–67% for the thiadiazolidine 1,1-dioxides over the
three steps (Table 1) were obtained.
conducted at 65°C, or if solvents other then acetonitrile
are used. The volatiles were removed by rotary evapo-
ration and no attempt was made to further purify or
characterize the intermediate monoalkylsulfamyl chlo-
rides, which were used immediately in the next step.
Diethyl ether is the preferred solvent in the formation
of the sulfamides and other than the aqueous workup
In the first step, lower yields are obtained with less than
5 equivalents of sulfuryl chloride, when the reaction is
Table 1. The synthesis of 1,2,5-thiadiazolidine 1,1-dioxidesa

P. D. Johnson et al. / Tetrahedron Letters 44 (2003) 5483–5485
5485
chloroalkylamines, sulfuryl chloride, and primary alkyl
or aryl amines.
References
1. Regainia, Z.; Abdaoui, M.; Aouf, N.-E.; Dewynter, G.;
Montero, J.-L. Tetrahedron 2000, 56, 381.
Scheme 3.
2. (a) Foster, A. B.; Duxbury, J. M.; Inch, T. D.; Webber, J.
M. J. Chem. Soc., Chem. Commun. 1967, 1, 881; (b)
McDermott, S. D.; Spillane, W. J. Org. Prep. Proced. Int.
1984, 16, 49; (c) Atkins, G. M., Jr.; Burgess, E. M. J. Am.
Chem. Soc. 1972, 94, 6135.
3. Hansen, N. C. Acta. Chem. Scand. 1963, 17, 2141.
4. Selected data: 2-phenyl-1,2,5-thiadiazolidine 1,1-dioxide, 4c:
mp 128–129°C; 1H NMR (300 MHz, CDCl3) l 7.37 (m,
2H), 7.24 (m, 2H), 7.15 (t, J=6.0 Hz, 1H), 4.57 (bs, 1H),
3.93 (t, J=5.3 Hz, 2H), 3.71 (m, 2H); C8H10N2O2S, calcd
C, 48.57; H, 5.08; N, 14.13. Found: C, 48.47; H, 5.11; N,
14.13. 2-phenyl-1,2,6-thiadiazinane 1,1-dioxide, 8a: mp 154-
155°C; 1H NMR (300 MHz, CDCl3) l 7.2–7.4 (m, 5H),
4.37 (t, J=6.0 Hz, 1H), 3.76 (t, J=6.3 Hz, 2H), 3.6–3.7
(m, 2H), 1.97 (m, 2H); C9H12N2O2S, calcd C, 50.93; H,
5.70; N, 13.20. Found: C, 50.96; H, 5.77; N, 13.20.
no further purification was necessary. The resulting
product 5 was characterized by LC/MS and was gener-
ally quite clean. The ring closure of 5 to 6 may be
accomplished with triethylamine in acetonitrile,
although the formation of the cyclosulfamide is slower
and yields are somewhat diminished. The final product
was purified by flash chromatography.
In addition, 1,2,6-thiadiazinanes may be prepared by
this method in similar yields (Scheme 3).4
In conclusion, we have developed a simple, efficient
synthesis of N-alkyl or N-aryl 1,2,5-thiadiazolidine and
1,2,6-thiadiazinane 1,1-dioxides from readily available